There have been known methods for synthesizing 5-iodo-2-methylbenzoic acid, such as a method in which 2-methylbenzoic acid is reacted with iodine in the co-presence of sodium nitrite and fuming sulfuric acid (Journal of the Indian Chemical Society (1930), p. 503 to 504) and a method in which 2-methylbenzoic acid is reacted with potassium iodide in the co-presence of thallium(III) trifluoroacetate (Journal of the Chemical Society. Perkin Transactions I. (1974), p. 2405 to 2409). The former method attains a yield as remarkably low as 18% and employs a large amount of a mixture of sodium nitrite and fuming sulfuric acid, serving as strong oxidizing agents (reaction reagent), requiring safe handling of the mixture. The latter method attains a yield as low as 33% and employs a highly toxic thallium salt, making the method inappropriate for producing 5-iodo-2-methylbenzoic acid on an industrial scale.
Other possible approaches are iodination techniques generally employed for aromatic compounds, such as the Sandmayer process in which an aromatic amine is subjected to diazo removal and iodination (Organic Syntheses, Collective Vol. II (1943), p. 351); the transhalogenation method in which chlorination or bromination is performed, followed by substitution of Cl or Br by I (Organic Syntheses, Collective Vol. V (1973), p. 478); a method employing iodine monochloride (Russian Journal of Organic Chemistry, 34, 7 (1998), p. 997 to 999); and methods in which iodine and sodium periodate are employed in the presence of an acid catalyst (Bulletin of the Chemical Society of Japan, vol. 73 (2000), p. 951 to 956, and Japanese Patent Application Laid-Open (kokai) No. 2003-12597).
In the case in which 5-iodo-2-methylbenzoic acid is synthesized through the aforementioned Sandmayer process, a multi-step reaction including nitration, reduction, diazotization, and diazo removal-iodination must be performed. Steps such as nitration and diazotization are problematic in safety, making the overall process very cumbersome. The transhalogenation method requires two reaction steps and a purification step, making the overall process cumbersome. In addition, since sodium iodide, potassium iodide, or a similar iodine compound is used in a large, excessive amount for introduction of iodine, such an excessive compound must be separated and collected after completion of reaction through burdensome steps, thereby increasing production cost.
Meanwhile, the above method employing iodine monochloride is a simple method which can be carried out through a single-reaction step. However, when iodine monochloride is reacted with an aromatic compound having an electron-attractive group such as a benzoic acid compound, high reaction efficiency cannot be attained, due to low reactivity. For example, the document disclosing the aforementioned method employing iodine monochloride describes iodination of benzoic acid, with the yield of 3-iodo-benzoic acid as a product being about 43%, which is unsatisfactory. When the method is applied to iodination of 2-methylbenzoic acid, high yield is difficult to attain.
As mentioned above, iodination methods employing iodine and an oxidizing agent such as iodic acid or periodic acid are conventionally known. For example, in the method wherein iodine and sodium periodate are employed in the presence of an acid catalyst (Bulletin of the Chemical Society of Japan, vol. 73 (2000), p. 951 to 956), a comparatively high reaction efficiency can be attained even when an aromatic compound having an electron-attractive group is reacted. However, since the method employs a large amount of sulfuric acid, burdensome treatment of waste sulfuric acid must be performed after reaction. Thus, in practice the iodination methods are not employed on an industrial scale.
The aforementioned Japanese Patent Application Laid-Open (kokai) No. 2003-12597 discloses a similar iodination method. In the method, 2-methylbenzoic acid is reacted with iodine and periodic acid in the presence of an acid catalyst, to thereby produce a mono-iodated methylbenzoic acid compound. However, product yield described in the Examples is about 52 to 65%, which is unsatisfactory. In addition, purity of the product is as low as about 95%. Thus, in order to obtain high-purity product, an additional purification step is required, making the overall process cumbersome. In this method, a considerable amount of the product still remains dissolved in mother liquor after recovery of the product. Since the mother liquor also contains sulfuric acid serving as a catalyst and other high-boiling-point compounds, separation and recovery of the product is difficult. The above document discloses a technique of recycling the mother liquor in the reaction system, but purity of the product decreases to 90%. Thus, the recycling is not considered appropriate. As described hereinabove, the method disclosed in Japanese Patent Application Laid-Open (kokai) No. 2003-12597 includes an improved step, but still has problems in being carried out on an industrial scale, and process cost remains to be improved.
Upon production of 5-iodo-2-methylbenzoic acid, 3-iodo-2-methylbenzoic acid, which is an isomer of iodo-methylbenzoic acid, is produced as a by-product. Since this isomer is difficult to separate from 5-iodo-2-methylbenzoic acid, 5-iodo-2-methylbenzoic acid of high purity is difficult to obtain. Thus, product purity and isolation yield are problematically unsatisfactory. The aforementioned conventional techniques do not suggest reduction in amounts of undesired isomers. There have already been known some techniques for site-specific iodination of an aromatic compound; e.g., methods including reacting iodine monochloride with an aromatic compound in the presence of zeolite (Catalysis Letters, 40 (1996), p. 257) and methods including oxyiodination of an aromatic compound in the presence of zeolite (Japanese Patent Application Laid-Open (kokai) No. 59-219241 and Japanese Kohyo Patent Publication No. 1-502819). However, in employment of any of these methods, selectivity of reaction is not always satisfactorily attained. In addition, there are very few reports about such reaction of compounds each having a plurality of substituents and an electron-attractive group (e.g., 2-methylbenzoic acid). Thus, according to conventional techniques, an effective method for producing 5-iodo-2-methylbenzoic acid which attains high selectivity and high yield on the basis of iodine has never been developed.
Thus, an object of the present invention is to provide a high-efficiency industrial means for producing 5-iodo-2-methylbenzoic acid through iodination of 2-methylbenzoic acid serving as a starting material, which means is a simple production process and is able to provide a high-purity product at high yield.